Among the steroid hormones, the androgens are reponsible for all the physical characteristics distinguishing male individuals from the female ones. In male individuals two steroids, testosterone and its reduced metabolite, i.e. dihydrotestosterone (abbreviated: DHT) are primarily responsible for the androgenic effects. In the tissues of mammals, the transformation of testosterone into DHT is catalyzed by the steroid 5.alpha.-reductase enzyme in the presence of nicotinamide adenine dinucleotide phosphate (NADPH). In male individuals, testosterone is predominantly synthetized by the testicles, wherefrom it is carried to the various tissues by the blood flow. In a part of the androgen-sensitive tissues where a significant activity of the steroid 5.alpha.-reductase enzyme can be detected, e.g. in the prostatic and skin tissues, the direct mediator of the androgenic effect is dihydrotestosterone which is synthetized in situ from testosterone taken up from the blood flow.
The increase of the DHT concentration in the tissues plays a role in the development and persistence of a number of androgen-dependent diseases, such as e.g. benign prostatic hyperplasia, acne, seborrhea, female hirsutism and androgenic alopecia [J. Clin. Invest. 49, 1737 (1970); J. Invest. Dermatol. 56, 366 (1971); J. Endocr. 75, 83 (1977); as well as Clin. in Dermatol. 6, 122 (1988)]. All substances inhibiting the steroid 5.alpha.-reductase enzyme and thereby diminishing the concentration of DHT in the tissues, may be useful for the treatment of the above DHT-dependent diseases.
Based on this recognition, research was directed to the synthesis of 5.alpha.-reductase enzyme inhibitors. In the last fifteen years many 5.alpha.-reductase enzyme inhibitors containing the steroid skeleton have been described in the literature.
The largest group of 5.alpha.-reductase inhibitors known until now is represented by the 4-aza-17-carbamoyl steroids.
A compound containing the 4-aza structural moiety is described in the U.S. Pat. No. 4,377,584 and in J. Steroid Biochem. 19, pages 385 to 390 (1983).
The synthesis of 17.beta.-(N,N-diethylcarbamoyl)-4-methyl-4-aza-5.alpha.-androstan-3-one is emphasized in the U.S. Pat. No. 4,220,775. On the basis of literature data this compound was subjected to a comprehensive biological study.
The synthesis of novel 17.beta.-(N-monosubstituted carbamoyl)-4-aza-5.alpha.-androstenones, e.g. 17.beta.-[N-(1,1-dimethylethyl)carbamoyl]-3-oxo-4-aza-5.alpha.-androst-1-e ne [compound of code No. MK-906, named Finasteride] is described in the European patent specification No. 155,096. Nowadays, the above compound has been accepted for therapeutical use.
The synthesis of oxidized analogues of 17.beta.-(N-monosubstituted carbamoyl)-4-aza-5.alpha.-androstan-3-one derivatives are published in the European patent specification No. 271,220. It is characteristic of the compounds described that the alkyl substituent of the 17.beta.-(N-monosubstituted carbamoyl) moiety may bear a hydroxyl, carboxyl or alkoxycarbonyl group.
The synthesis and use for the treatment of alopecia of 17.beta.-(N-monosubstituted carbamoyl)-4-aza-5.alpha.-androst-1-en-3-one derivatives are described in the European patent specification No. 285,382; whereas the use of the above compounds for the treatment of prostate carcinoma is suggested in the European patent specification No. 285,383.
A novel process for building-up the aminocarbonyl side chain in position 17 of 17.beta.-substituted-3-oxo-4-azasteroids via the Grignard reaction of the imidazole derivative of the appropriate carboxylic acid is presented in the European patent specification No. 367,502.
The European patent specification No. 462,662 discloses the synthesis of 17.beta.-(N-monosubstituted adamantylcarbamoyl)- as well as (norbornylcarbamoyl)-4-aza-5.alpha.-androst-1-en-3-one and -4-aza-5.alpha.-androstan-3-one. In the patent specifications, the possibilities of use of the 5.alpha.-reductase-inhibiting compounds are also discussed.
The synthesis of 4-azasteroids containing double bond(s) in the positions 8(14), 7(8) or 16(17) and/or 1(2) is described in the European patent specification No. 277,002. A characteristic structural moiety of the C.sub.17 -side chain is the aminocarbonyl group, but another side chain containing oxygen or nitrogen may also be present in position 17.
The combination of aromatase inhibitors with 5.alpha.-reductase inhibitors is suggested for the treatment of prostatic hyperplasia in the German patent specification No. 3,607,651. 1-Methylandrosta-1,4-diene-3,17-dione as aromatase inhibitor and 17.beta.-(N,N-diethylcarbamoyl)-4-methyl-4-aza-5.alpha.-androstan-3-one as 5.alpha.-reductase inhibitor are recommended.
The topical usability of 5.alpha.-reductase inhibitors is suggested in the U.S. Pat. No. 4,885,289.
In the PCT patent application published under No. WO 91/12261, the synthesis of 4-azasteroids is disclosed, the C.sub.17 -side chain of which is different from those previously described. A characteristic example of these compounds is 4-methyl-17.beta.-[N-isopropyl-N-(N,N-diisopropylcarbamoyl)carbamoyl]-4-az a-5.alpha.-androstan-3-one.
The synthesis of novel 4-azasteroids bearing a C.sub.17 -side chain of formula --X--COZ is published in the European patent specification No. 200,859. In this formula X means a chemical bond or a straight or branched C.sub.1-6 aliphatic chain and Z stands for an alkoxy or a substituted amino group. These compounds may contain also an oxo group in position 12 of the steroid skeleton.
The Hungarian patent application No. 3396/91 (published under No. T/59417) relates to the synthesis of 4-azasteroid derivatives containing a C.sub.17 -aminocarbonyl side chain bearing an alkyl group substituted by an aromatic group. These compounds are useful for the treatment and prevention of prostatic hypertrophia.
Various types of azasteroids mainly inhibiting 5.alpha.-reductase is summarized in J. Med. Chem. 27, pages 1690 to 1701 (1984). This summary contains biological data, too.
The structure-activity relationship of 5.alpha.-reductase inhibitors containing the 4-aza structural moiety is discussed in J. Med. Chem. 29, pages 2298 to 2315 (1986).
The 5.alpha.-reductase-inhibiting activity and the biological effect of antiandrogenic properties of 4-azasteroids observed on rats are summarized in Steroids 47/1, pages 1 to 19 (1986).
The transformation of acylimidazole derivatives, mainly to carboxamide derivatives is published in Synt. Comm. 30(17), pages 2683 to 2960 (1990).
The high number of the above-cited literature and patent documents also support the importance of 5.alpha.-reductase inhibitors.